Project Abstract Protein inactivating mutations of the BRCA1 gene are associated with elevated breast and ovarian cancer risks. However there is considerable uncertainty about the effects of other BRCA1 variants, particularly the single base changes that alter amino acids of the protein, termed nonsynonymous unclassified variants (ns UCVs). Because these variants are rare, no single source of data is sufficiently informative to unambiguously classify them as either neutral or pathogenic. Our goal is to assess the feasibility of adding useful new information about the risks of ns UCVs of BRCA1 by assessing cancer incidence in first-degree (FD) relatives of a population-based multi-ethnic series of incident breast cancer cases with and without ns UCVs. Our specific aims are: 1) to compare the prevalence and types of ns UCVs detected among Hispanic, Asian- American, African-American and non-Hispanic white (NHW) breast cancer cases ascertained from the Northern California component of the Breast Cancer Family Registry (Breast CFR); 2) to estimate risk ratios and standardized residuals for BRCA1-related cancers among FD relatives of 66 cases who carry ns UCVs, compared to those of 1729 cases who carry at most neutral polymorphisms; 3) to combine results of Aim 2 with available pathogenicity scores of the variants to classify them as benign or deleterious; and 4) to evaluate agreement between this classification and one obtained using a function-based statistical learning algorithm. Our ultimate goal is to assess the potential of using cancer incidence in relatives of carriers to help classify other variants in disease-susceptibility genes. If we find that the results of this feasibility study are promising, we will seek separate funding to extend it to other UCVs of BRCA1 and BRCA2, using a larger series of population-based families from the Breast CFR and other population-based breast and ovarian cancer family registries. Project Narrative The risks associated with unclassified variants of established disease-susceptibility genes have important clinical implications, particularly for Hispanic and nonwhite populations, whose risks have not been extensively studied. This study will examine the feasibility of adding new information about these risks using cancer data from relatives of variant carriers.